Breast Cancer and the genetics of BRCA
If there is this gene in the family, absolutely do not tell your
children. If you want them tested, then do it secretly and do not
tell them until they are 20 yr old. That is when they would be
start to be screened. A teenager does not need to think about
removing their breasts.
BRCA genetics in Breast and
A woman’s lifetime risk of
developing breast and/or ovarian cancer is greatly increased if she
inherits a harmful mutation in BRCA1 or BRCA2. Such a
woman has an increased risk of developing breast and/or ovarian cancer
at an early age and often has multiple, close family members who have
been diagnosed with these diseases. Harmful BRCA1 mutations may
also increase a woman’s risk of developing cervical, uterine,
pancreatic, and colon cancer. Harmful BRCA2 mutations may
additionally increase the risk of pancreatic cancer, stomach cancer,
gallbladder and bile duct cancer, and melanoma. These mutations are
thought to be responsible for an estimated 5 to 7% of all breast and
Men with harmful BRCA1
mutations also have an increased risk of breast cancer and, possibly, of
pancreatic cancer, testicular cancer, and early-onset prostate cancer.
However, male breast cancer, pancreatic cancer, and prostate cancer
appear to be more strongly associated with BRCA2 gene
The likelihood that a breast and/or
ovarian cancer is associated with a harmful mutation in BRCA1
or BRCA2 is highest in families with a history of multiple
cases of breast cancer, cases of both breast and ovarian cancer, one or
more family members with two primary cancers, or an Ashkenazi (Eastern
European) Jewish background. However, not every
woman in such families carries a harmful BRCA1 or BRCA2
mutation, and not every cancer in such families
is linked to a harmful mutation in one of these genes. Furthermore,
not every woman who has a harmful BRCA1
or BRCA2 mutation will develop breast and/or ovarian cancer.
According to estimates of lifetime
risk, about 12 percent of women in the general population will develop
breast cancer sometime during their lives compared with about 60 percent
of women who have inherited a harmful mutation in BRCA1 or
Lifetime risk estimates for ovarian
cancer among women in the general population indicate that 1.4 percent
will be diagnosed with ovarian cancer compared with 15 to 40 percent of
women who have a harmful BRCA1 or BRCA2 mutation.
It is important to note, however,
that most research related to BRCA1 and BRCA2 has been
done on large families with many individuals affected by cancer.
Estimates of breast and ovarian cancer risk associated with BRCA1
and BRCA2 mutations have been calculated from studies of these
families. No data are available from long-term studies of the general
population comparing cancer risk in women who have harmful BRCA1
or BRCA2 mutations with women who do not have such mutations.
Therefore, the percentages given above are estimates that may change as
more data become available.
Mutations in several other genes,
including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and
MSH2, have been associated with hereditary breast and/or
ovarian tumors. However, the majority of hereditary breast cancers can
be accounted for by inherited mutations in BRCA1 and BRCA2.
Who should be tested for BRCA
Currently, there are no
standard criteria for recommending or referring someone for BRCA1
or BRCA2 mutation testing. In a family with a history of breast
and/or ovarian cancer, it may be most informative to first test a family
member who has breast or ovarian cancer. If that person is found to have
a harmful BRCA1 or BRCA2 mutation, then other family
members can be tested to see if they also have the mutation.
Regardless, women who have a
relative with a harmful BRCA1 or BRCA2 mutation and
women who appear to be at increased risk of breast and/or ovarian cancer
because of their family history should consider genetic counseling to
learn more about their potential risks and about BRCA1 and
BRCA2 genetic tests.
The likelihood of a harmful mutation
in BRCA1 or BRCA2 is increased with certain familial
patterns of cancer. These patterns include the following:
- For women who
are not of Ashkenazi Jewish descent:
first-degree relatives (mother, daughter, or sister) diagnosed
with breast cancer, one of whom was diagnosed at age 50 or
- three or
more first-degree or second-degree (grandmother or aunt)
relatives diagnosed with breast cancer regardless of their age
combination of first- and second-degree relatives diagnosed with
breast cancer and ovarian cancer (one cancer type per person);
first-degree relative with cancer diagnosed in both breasts
(bilateral breast cancer);
combination of two or more first- or second-degree relatives
diagnosed with ovarian cancer regardless of age at diagnosis;
- a first-
or second-degree relative diagnosed with both breast and ovarian
cancer regardless of age at diagnosis; and
cancer diagnosed in a male relative.
- For women of
Ashkenazi Jewish descent:
first-degree relative diagnosed with breast or ovarian cancer;
second-degree relatives on the same side of the family diagnosed
with breast or ovarian cancer.
These family history patterns apply
to about 2 percent of adult women in the general population. Women who
have none of these family history patterns have a low probability of
having a harmful BRCA1 or BRCA2 mutation.
Several options are
available for managing cancer risk in individuals who have a harmful
BRCA1 or BRCA2 mutation. However, high-quality data on the
effectiveness of these options are limited.
means cancer screening, or a way of detecting the disease early.
Screening does not, however, change the risk of developing cancer.
The goal is to find cancer early, when it may be most treatable.
However, because BRCA carriers are prone to developing
fast-growing tumors, even with this surveillance, about 25% to 30%
of carriers are diagnosed when the tumor is already more than 2 cm
in diameter, she noted. The MRI is expensive in itself, but useful
because it can detect very small tumors that might not be picked up
otherwise. It also detects many other abnormalities that are not
cancer, and this implies not just extra cost but also considerable
anxiety for the women concerned. Dr. Kamm and colleagues outlined
the results for 196 women with BRCA gene mutations who had
been screened between 1999 and 2005. The women were screened for a
median period of 2 years, and in total underwent 1149 breast
examinations (of which 2% were abnormal), 494 mammograms (9%
abnormal), and 436 MRI scans (14% abnormal). When any abnormality
was found, the women underwent further investigation, which led to
another 32 breast examinations, 17 mammograms, 64 MRI scans, 114
ultrasound examinations, and 48 biopsies. During the 6-year period,
13 cancers were found, 11 of which were invasive.
type of surgery involves removing as much of the "at-risk" tissue as
possible in order to reduce the chance of developing cancer.
Bilateral prophylactic mastectomy (removal of healthy breasts) and
prophylactic salpingo-oophorectomy (removal of healthy fallopian
tubes and ovaries) do not, however, offer a guarantee against
developing cancer. Not all at-risk tissue can be removed by these
procedures. Currently, about half the women who carry the BRCA
gene mutation opt for this measure. Women who carry the BRCA
gene mutation have an estimated 85% lifetime risk of developing
breast cancer, but a prophylactic mastectomy reduces this risk to
less than 1%.
behaviors have been associated with breast and ovarian cancer risk
in the general population. Research results on the benefits of
modifying individual behaviors to reduce the risk of developing
cancer among BRCA1 or BRCA2 mutation carriers are
approach involves the use of natural or synthetic substances to
reduce the risk of developing cancer or to reduce the chance that
cancer will come back. For example, the drug tamoxifen has been
shown in numerous clinical studies to reduce the risk of developing
breast cancer by about 50 percent in women who are at increased risk
of this disease. Another drug, raloxifene, was shown in a large
clinical trial sponsored by the National Cancer Institute (NCI) to
reduce the risk of developing invasive breast cancer in
postmenopausal women at increased risk of this disease by about the
same amount as tamoxifen.
Opinions about prophylactic
Researchers conducted a
study that surveyed 312 women who received genetic counseling and were
screened for BRCA mutations at the M. D. Anderson Cancer Center between
1997 and 2005. Of those surveyed, 70% (217 women) had breast cancer and
28% (86 women) tested positive for a BRCA mutation.
The survey included questions
regarding the fear of developing the disease as well as feelings
regarding screening techniques (mammogram and breast self-exam) and
prophylactic strategies (tamoxifen [Nolvadex®] and prophylactic
mastectomy). The researchers compared the responses of women who were
BRCA positive and those who were BRCA negative.
Among BRCA positive women, 70% felt
that prophylactic mastectomy was the most effective way to reduce their
risk of breast cancer compared with 40% of BRCA negative women.
Furthermore, 64.7% of BRCA-positive women felt that prophylactic
mastectomy was the only way to reduce their worry regarding the disease
compared with 34.4% of BRCA-negative women.
There were no
significant differences between the two groups regarding feelings about
mammograms, breast self-exams, or tamoxifen; however, feelings about
prophylactic surgery appeared to be drastically different and appeared
to be driven primarily by worry among BRCA-positive women. Of the women
who felt that prophylactic mastectomy was the best way to reduce their
risk, 81% underwent the surgery (compared with 19.1% of those who
disagreed); and of the women who felt that the surgery was the only way
to reduce their worry, 84.2% proceeded with surgery (compared with 15.8%
of those who disagreed).
Factors that increase cancer in
The following factors
have been associated with increased or decreased risk of developing
breast and/or ovarian cancer in the general population. It is not yet
known exactly how these factors influence risk in people with BRCA1
or BRCA2 mutations. In addition, a significant portion of
hereditary breast cancers are not associated with BRCA1 or
risks of breast and ovarian cancer increase with age. Most breast
and ovarian cancers occur in women over the age of 50. Women with
harmful BRCA1 or BRCA2 mutations often develop
breast or ovarian cancer before age 50.
who have a first-degree relative (mother, sister, or daughter) or
other close relative with breast and/or ovarian cancer may be at
increased risk of developing these cancers. In addition, women with
relatives who have had colon cancer may be at increased risk of
developing ovarian cancer.
who have already had breast cancer are at increased risk of
developing breast cancer again, or of developing ovarian cancer.
is a hormone that is naturally produced by the body and stimulates
the normal growth of breast tissue. It is thought that excess
estrogen may contribute to breast cancer risk because of its natural
role in stimulating breast cell growth.
Control Pills (Oral Contraceptives)—Most
studies have shown a slight increase or no change in risk of breast
cancer among women taking birth control pills. In contrast, numerous
studies have shown that taking birth control pills decreases a
woman’s risk of developing ovarian cancer. This protective benefit
appears to increase with the duration of oral contraceptive use and
persists up to 25 years after discontinuing use. It also appears
that the use of birth control pills lowers the risk of ovarian
cancer in women who carry harmful BRCA1 or BRCA2
Hormone Replacement Therapy—Doctors
may prescribe hormone replacement therapy (HRT) to reduce the
discomfort of certain symptoms of menopause, such as hot flashes.
However, the results of the Women’s Health Initiative (WHI), a large
clinical study conducted by the National Heart, Lung, and Blood
Institute, part of the National Institutes of Health (NIH), showed
that HRT with the hormones estrogen and progestin is associated with
harmful side effects, including an increased risk of breast cancer
and increased risks of heart attack, blood clots, and stroke. The
WHI also showed that HRT with estrogen alone was associated with
increased risks of blood clots and stroke, but the effect on breast
cancer risk was uncertain. Because of these potential harmful side
effects, the FDA has recommended that HRT be used only at the lowest
doses for the shortest period of time needed to achieve treatment
goals. No data have been reported to date regarding the effects of
HRT on breast cancer risk among women carrying harmful
mutations, and only limited data are available regarding HRT use and
ovarian cancer risk among such women. In one study, HRT use did not
appear to affect ovarian cancer risk among women with
increasing breast cancer:
evidence indicates that obesity is associated with an increased risk
of breast cancer, especially among postmenopausal women who have not
used HRT. Evidence also suggests that obesity is associated with
increased mortality (death) from ovarian cancer.
studies have examined the relationship between physical activity and
breast cancer risk, and most of these studies have shown that
physical activity, especially strenuous physical activity, is
associated with reduced risk. This decrease in risk appears to be
more pronounced in premenopausal women and women with
lower-than-normal body weight.
substantial evidence that alcohol consumption is associated with
increased breast cancer risk. However, it is uncertain whether
reducing alcohol consumption would decrease breast cancer risk.
early studies suggested a possible association between a high-fat
diet and increased breast cancer risk, more recent studies have been
inconclusive. In the WHI, a low-fat diet did not help reduce breast
Cancer in Men
Carcinoma of the male
breast has many similarities to breast cancer in women, but the diseases
have different genetic and pathologic features. Both BRCA1 and BRCA2
mutations can cause breast cancer in women, but only BRCA2 mutations
confer a significant risk to men. Although older articles have reported
that men with breast cancer have poorer survival rates than women, most
recent series show that men and women have equivalent prognoses when
matched for age and stage of disease. Prophylactic mastectomy of the
contralateral breast may be indicated in a man with breast cancer.
However, there is no published clinical data or evidence-based
guidelines on prophylactic mastectomy for men with a BRCA2 mutation or a
family history of breast cancer. It has been estimated that
approximately 6 percent of men who are positive for BRCA2 will develop
breast cancer by the age of 70. This is about equal to the risk of
breast cancer in average-risk women without BRCA mutations. This
difference in risk of breast cancer between BRCA-positive women and men
may be due to the fact that men have much less breast tissue and serum
estrogen than women.